Sleep is a vital biological event that engages both the brain and body for long periods of time daily throughout life. In spite of sleep's importance, the consequences of sleep deprivation are not well delineated. In our animal laboratory, we study the physiological effects of sleep loss and the mechanisms by which the brain and body attempt to compensate for lost sleep. We now know that the major symptoms of prolonged sleep loss are specific and develop in all sleep-deprived rats: energy expenditure doubles, symptoms resembling protein deficiency develop, and temperature regulation fails. Increased plasma alkaline phosphatase (ALP), an enzymatic marker for bone and liver disease, is the only clinical chemistry parameter identified to date that changes early and dramatically; further study of the ALP organ source may reveal the nature of an early biochemical change. We have determined that the protein deficiency symptoms are secondary to the energy expenditure rise. Providing a calorie-dense diet to rats during sleep deprivation causes hyperphagia, which does not occur under normal conditions, and which delays development of protein deficiency symptoms and prolongs survival. Provision of a protein-augmented diet, however, has no such effect. One possible mediator of the increased energy expenditure is thyroid hormone (T4). The response of thyroid-stimulating hormone (TSH) to thyrotropin-releasing hormone (TRH) stimulation in sleep- deprived rats is neither augmented, as expected from low peripheral T4 (i.e., evidence of central hypothyroidism), nor blunted, because of a caloric deficit manifested by weight loss. Even though whole body metabolism increases, free (F) T4 declines and the ratio of free triiodothyronine (FT3) to FT4 increases, indicating a biological preference for metabolic activity. Increased T3 production from T4 is also indicated by 1) the maintenance of plasma FT3 together with low FT4 during caloric deficiency; 2) shorter half-life of T3 than T4; and, 3) both normal basal and stimulated plasma FT3 and TSH. Changes in brain metabolism do not parallel those of peripheral energy expenditure. In nearly all grey matter structures examined, rates of local cerebral glucose utilization tend to be lower than normal, despite an increase in deep brain temperature. Body temperature declines at the same time that peripheral energy expenditure increases, suggesting that a failure of heat retention mechanisms may be the driving force behind the rise in energy expenditure.